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Mammalian target of rapamycin inhibition enhances delivery and activity of antisense oligonucleotides in uveal melanoma cells

Shanna Dewaele, Louis Delhaye (UGent) , Boel De Paepe (UGent) , Bram Bogaert (UGent) , Ramiro Martinez (UGent) , Jasper Anckaert (UGent) , Nurten Yigit (UGent) , Justine Nuytens (UGent) , Rudy Van Coster (UGent) , Sven Eyckerman (UGent) , et al.
(2023) NUCLEIC ACID THERAPEUTICS. 33(4). p.248-264
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Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Owing to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is essential for UM cell survival and that antisense oligonucleotide (ASO)-mediated silencing of SAMMSON impaired cell viability and tumor growth in vitro and in vivo. By screening a library of 2911 clinical stage compounds, we identified the mammalian target of rapamycin (mTOR) inhibitor GDC-0349 to synergize with SAMMSON inhibition in UM. Mechanistic studies revealed that mTOR inhibition enhanced uptake and reduced lysosomal accumulation of lipid complexed SAMMSON ASOs, improving SAMMSON knockdown and further decreasing UM cell viability. We found mTOR inhibition to also enhance target knockdown in other cancer cell lines as well as normal cells when combined with lipid nanoparticle complexed or encapsulated ASOs or small interfering RNAs (siRNAs). Our results are relevant to nucleic acid treatment in general and highlight the potential of mTOR inhibition to enhance ASO and siRNA-mediated target knockdown.
Keywords
lipid nanoparticle, siRNA, ASO, compound, oncology, combination therapy

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MLA
Dewaele, Shanna, et al. “Mammalian Target of Rapamycin Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells.” NUCLEIC ACID THERAPEUTICS, vol. 33, no. 4, 2023, pp. 248–64, doi:10.1089/nat.2023.0008.
APA
Dewaele, S., Delhaye, L., De Paepe, B., Bogaert, B., Martinez, R., Anckaert, J., … Mestdagh, P. (2023). Mammalian target of rapamycin inhibition enhances delivery and activity of antisense oligonucleotides in uveal melanoma cells. NUCLEIC ACID THERAPEUTICS, 33(4), 248–264. https://doi.org/10.1089/nat.2023.0008
Chicago author-date
Dewaele, Shanna, Louis Delhaye, Boel De Paepe, Bram Bogaert, Ramiro Martinez, Jasper Anckaert, Nurten Yigit, et al. 2023. “Mammalian Target of Rapamycin Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells.” NUCLEIC ACID THERAPEUTICS 33 (4): 248–64. https://doi.org/10.1089/nat.2023.0008.
Chicago author-date (all authors)
Dewaele, Shanna, Louis Delhaye, Boel De Paepe, Bram Bogaert, Ramiro Martinez, Jasper Anckaert, Nurten Yigit, Justine Nuytens, Rudy Van Coster, Sven Eyckerman, Koen Raemdonck, and Pieter Mestdagh. 2023. “Mammalian Target of Rapamycin Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells.” NUCLEIC ACID THERAPEUTICS 33 (4): 248–264. doi:10.1089/nat.2023.0008.
Vancouver
1.
Dewaele S, Delhaye L, De Paepe B, Bogaert B, Martinez R, Anckaert J, et al. Mammalian target of rapamycin inhibition enhances delivery and activity of antisense oligonucleotides in uveal melanoma cells. NUCLEIC ACID THERAPEUTICS. 2023;33(4):248–64.
IEEE
[1]
S. Dewaele et al., “Mammalian target of rapamycin inhibition enhances delivery and activity of antisense oligonucleotides in uveal melanoma cells,” NUCLEIC ACID THERAPEUTICS, vol. 33, no. 4, pp. 248–264, 2023.
@article{01HN35VN3XBBADAYTHND9EC9YJ,
  abstract     = {{Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Owing to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is essential for UM cell survival and that antisense oligonucleotide (ASO)-mediated silencing of SAMMSON impaired cell viability and tumor growth in vitro and in vivo. By screening a library of 2911 clinical stage compounds, we identified the mammalian target of rapamycin (mTOR) inhibitor GDC-0349 to synergize with SAMMSON inhibition in UM. Mechanistic studies revealed that mTOR inhibition enhanced uptake and reduced lysosomal accumulation of lipid complexed SAMMSON ASOs, improving SAMMSON knockdown and further decreasing UM cell viability. We found mTOR inhibition to also enhance target knockdown in other cancer cell lines as well as normal cells when combined with lipid nanoparticle complexed or encapsulated ASOs or small interfering RNAs (siRNAs). Our results are relevant to nucleic acid treatment in general and highlight the potential of mTOR inhibition to enhance ASO and siRNA-mediated target knockdown.}},
  author       = {{Dewaele, Shanna and Delhaye, Louis and De Paepe, Boel and Bogaert, Bram and Martinez, Ramiro and Anckaert, Jasper and Yigit, Nurten and Nuytens, Justine and Van Coster, Rudy and Eyckerman, Sven and Raemdonck, Koen and Mestdagh, Pieter}},
  issn         = {{2159-3337}},
  journal      = {{NUCLEIC ACID THERAPEUTICS}},
  keywords     = {{lipid nanoparticle,siRNA,ASO,compound,oncology,combination therapy}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{248--264}},
  title        = {{Mammalian target of rapamycin inhibition enhances delivery and activity of antisense oligonucleotides in uveal melanoma cells}},
  url          = {{http://doi.org/10.1089/nat.2023.0008}},
  volume       = {{33}},
  year         = {{2023}},
}
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